Simultaneous haloalkylation and reduction of organic compounds



Patented Nov. 1, 1949 SIMULTANEOUS HALOALKYLATION AND REDUCTION OF ORGANIC COMPOUNDS Leonard Weislerand Albert J. Chechak, Rochester, N.'Y., assignors to Distillation Products, Inc., Rochester, N. Y., a corporation of Delaware No Drawing. Application May 20, 1949,

Serial No. 94,536 Y Claims. 1

This invention has for its object to provide a new and useful method for the haloalkylation and reduction of organic compounds containing not more than two benzenoid rings. Another object is to provide an improved process for the conversion of tocopherol material characterized by'having at least one aromatic hydrogen atom on the nucleus thereof to alpha-tocopherol. Other objects will appear hereinafter.

These and other objects are accomplished in accordance with our invention which includes the haloalkylation of an aromatic compoundby reacting said compound with an aldehyde and hydrogen halide in the presence of stannous chloride which reduces the haloalkylated compound simultaneously with the formation of said haloalkylated compound.

In the following examples and description we have set forth the preferred embodiment of our invention but it is understood this is in illustration and not in limitation thereof.

It is known that the low potency tocopherols, beta-tocopherol, gamma-'tocopherol and deltatocopherol, which are characterized by having at least one aromatic hydrogen atom on the nucleus can be converted to alpha-tocopherol by. chloromethylation and reduction. This has been accomplished in the past by dissolving such a low potency tocopherol, as for example gammatocopherol, in ether, .orsuitablesolvent, adding aqueous. formaldehyde, concentrated hydrochloric acid, and stirring for 2 hours. At the end of this chloromethylation period, zinc dust is added directly to the reaction mixture and reduction allowed to proceed for 30 minutes. The mixture is then washed with water and the ether solution of tocopherol dried and evaporated. The alpha-tocopherol is then concentrated by molecular distillation.

Instead of the two-stage process consisting of chloromethylation and separatereduct'ion formerly employed, we now carry out the chloromethylation and reduction reactions simultaneously in a single-stage process. 'This .objective is accomplished by using stannous chloride as the reducing agent and introducinglt initially into the reaction mixture. stannous chloride acts selectively .to reduce the substituent haloalkyl group introduced into the material being haloalkylated while leaving reactants such as 2 formaldehyde unchanged. Consequently, the haloalkylation is allowed to proceed unhindered and simultaneously therewith reduction of the haloalkylated product by stannous chloride takes place.

The chloromethylation reaction involves the replacement of the hydrogen atom in the 5 position of gamma-tocopherol by a substituent and is accomplished in the case of a methyl group, for example, by the reaction of the gamma-tocopherol with an ethereal solution of formaldehyde in the presence of hydrogen chloride or hydrochloric acid. This results in the introduction of a chloromethyl group. This group is then converted into the methyl group by a stannous chlobecause of dlfiiculties in handling it. Instead of using formalin, a polymer of formaldehyde, such as paraformaldehyde, may be used to introduce the chloromethyl group. chloromethyl ether, prepared by introducing hydrogen chloride gas into a mixture of paraformaldehydeand methanol, may also be used. Other groups than methyl may be introduced using other reactants of the type mentioned. Thus, the ethyl group can be introduced using paraldehyde or diethyl formal instead of dimethyl formal. It is to be understood that all such reactions which involve introduction of a halo-alkyl radical shall be included within the scope of our invention and within the meaning of the term haloalkylation as used herein.

' Similarly, beta-tocopherol is treated in accordance with this invention to introduce a hydrocarbon group in the 7 position on the nucleus; and delta-tocopherol, which has aromatic hydrogen atoms in both the 5 and 7 positions, is treated to replace either or both of such hydrogen atoms with 'a hydrocarbon group.

The use of a solvent increases the yield of alpha-tocopherol but the reactionmay be carried on satisfactorily in the absence of a solvent.

The use of stannous chloride as the reducing agent in a single-stage process is not limited to Whatweclaimis: tocopherol o pounds but is applicable to e ol. The process which com rises haloalkylatlng allwlation of aromatic compounds generally. the position of gamma-tocopherol by reacting In the following exiiiples We give the Pr therewith-analdehydeandahydrogen halide and ferred manner of eflecting conversion inaccord- 5' simultaneously reducing the resulting substituent ance with our invention but it i o e underhaloalkyl radical b means of stannous chloride. stood that theseare given in illustration and said aldehyde, hydrogen halide and stannous not in limitation thereof.- chloride being present in admixture during said reacting. Ewmp 1 l0 2. The process which comprises chloroalkylat- To a solution of g. of gamma-tocopherol ing the 5 position of g mmapher y mi concentrate in 75 cc. of ether is added 1.35 cc. s therewith an hyde and hydr en h r of formalin and cc. of concentrated hydroand simultaneously reducing he r lt n acid containing m; Simmons ch10- stituent chloroalkyl radical by means of stannous,

ride. The mixture is stirred for two hours at 18 oride, said 'stannous chloride being Present in room temperature and worked up by w hing 3'10 reaction mixture during said chloroalhlatwith water, dried. and evaporated. The mixture 8- resulting from the reaction is distilled inv a mo- The process which comprises chlor m lecular stillbetween Mil-220 C. at In to recover t the 5 P i ion 01 gamm y tocopherol. The gamma to alpha conversion ef- 2o acting therewi h a p nd lected from the is t 0 class consisting of formaldehyde and paraformala dehyde, and simultaneousl reducing the result- Example 2 i ing substituent chloromethyl radical by means of stannous chloride, said compound. hydrogen chlo- To a solution of 10.8 g. (0.1 mole) of anisole a ride and stannous chloride being present in 100cc. of ether, add 140 cc. of concentrated mixture during said reacting hydrochloric acid, 7.5 cc. of formalin. and The modes wmch comprises halmlkylam stanmus chlm'ide- The mixture is an aromatic compound containing not more than stirred for two hours at 5-10" C. and worked up two benzenoid rings by reacting therewith-an ab by Washing the ether solution Water and dehyde and a hydrogen halide nd filtering through a column of 130mm,, ly reducing the resulting substituent haloalkyl thetic sodium aluminum silicate to remove th radical by means of stannous chlorideg'said aid last traces of zinc chloride. The ether is rehyde, hydmgmhande and anxious/chloride moved and a-methoxy toluene separated from the mg present in a t r during said reacting,

. residue by fractional distillation. I 5 The process which comprises chlomalkylgtreaction mixture along with other icy-products.

. ing an aromatic compound containing not more Example 3 than :two benzenoid rings by reactingwith said A mixture of 300 g. (3.35 moles) of benzene; an aldehyde and 'hydmgen 30 g. (1 mole) of pafaformmdehyde 30 of pub and simultaneously reducing the resulting subverized zinc chloride, and 225 g. stannous chloride. Stiment chlor oak-71 radical means of ammo! is stirred and heated at 60 0. At this temperachlmider Said animus being Present ture a rapid stream of hydrogen chloride is pasisl fig "acme mixt, ure uring said chloroalkylat into the reaction mixture for about 25 minu The organic layer is worked up by washing with e process which mprises chloromethyl' water dilute sodium carbonate and then passed in ating an aromatic compound containing not more 1: than two benzenoid rings y reacting therewith thru a column of Doucil, a synthetic sodium aluminum silicate to remove zinc chloride. Byhydrogen chloride and/8' member selected m fractional distillation toluene is isolated from the the misting flirmaldehyde and formaldehyde, and simultaneously reducing the resulting substituent chloromethyl radical by means of stannous chloride, said stannous chlo- I ride being preesnt in the reaction mixture dur- To a solution of 10 g. of gamma-tocopherol coning said ehloromethylating. centrate in 75 cc. of ether. add 1 8mm of acetal- 7. 'The alkylation of the 5 position of gammadehyde and 6 grams of stannous chloride. This tocopherol by reacting therewithan aldehyde and mixture is stirred for 1% ho rs at room tempera- .a hydrogen halide in the presence of stannous ture during which time hydrogen chloride gas is chloride.

Example 4- bubbled through. The mixture is then washed 8. The methylation of the 5position of gammaiwith water, dried, and evaporated. Theresidue tocopherol by reacting therewith formaldehydeis distilled in a molecular still between 140-220 m and a hydrogen halide in the presence of stan- C. at 'I to recover a tocopherol with an ethyl nous chloride.

- group in the5position. 9. The addition of a methyl group to the 5 Similar results are obtained employing any orposition of gamma-tocopherol by contacting a garlic material capable of undergoing haloalkylsolution of gamma-tocopherol with .formaldehyde ation and including beta-tocopherol and deltaand hydrogen chloride in the presence of stantocopherol as well as'gamma-tocopherol. nouschloride:

. This application is a continuation-in-part of 10. The alkylation of the 7 position of betaour application Serial No. 667,736 flied May 6, tocopherolby reacting therewithanaldehyde and 1946, and now abandoned. a hydrogen halide in the presence of stannoua While the invention has been described in conchloride.

siderable detail with reference to certain pre-- 11. The methylation of the 7 position of betaferred embodiments thereof, it will be understood tocopherol "by reacting therewith formaldehyde that variations and modifications maybe effected and a hydrogen halide in the presence of stall-- within the spirit and scope of the invention as denous chloride. ilnedinthe appended claims. 12. The addition of a methyl group to the I s eow position or b'eta-tooopheroi by contacting a coin-- tion of beta-tocopherol with i'ormnldehyde and hydrogen chloride in the preaence or atnnnoua chloride.

1a. The alkylation or at least one or the a m '1 positions 01' delta-tocopheroi by reacting therewith an aldehyde and a hydrogen halide in the presence of stannous chloride.

14. The methyiation oi the 5 and 7 positions of delta-tocopheroi by reacting therewith iormaide- 10 h'rlicondahydrorenhalidointheprooenceoi otonnous chloride.

15. The addition oi a. methyl group to the 5 and 7 positions or delta-tocopheroi by contacting a solution or deita tocopheroi' with formaldehyde 

